Can non-heart-beating donors replace cadaveric heart-beating liver donors?

Forum on Liver Transplantation / Journal of Hepatology 45 (2006) 483 513 499 [12] Ryan CK, Johnson LA, Germin BI, Marcos A. One hundred consecutive hepatic biopsies in the workup of living donors for right lobe liver transplantation. Liver Transpl 2002;8:1114. [13] Tan HP, Patel-Tom K, Marcos A. Adult living donor liver transplantation: who is the ideal donor and recipient?. J Hepatol 2005;43:13. [14] Clavien PA. Third forum on liver transplantation. Living donor liver transplantation. Who needs it? How to do it? Who should do it?. J Hepatol 2005;43:11. [15] Portmann B, Wight DGD. Pathology of liver transplantation (excluding rejection). In: Calne R, editor. Liver Transplantation: The Cambridge and King s College Hospital Experience. Cambridge: Grune & Stratton; 1987. p. 437. [16] Ploeg RJ, D Alessandro AM, Knechtle SJ, Stegall MD, Pirsch JD, Hoffmann RM, et al. Risk factors for primary dysfunction after liver transplantation a multivariate analysis. Transplantation 1993;55:807. [17] Strasberg SM, Howard TK, Molmenti EP, Hertl M. Selecting the donor liver: risk factors for poor function after orthotopic liver transplantation. Hepatology 1994;20:829. [18] Fishbein TM, Fiel MI, Emre S, Cubukcu O, Guy SR, Schwartz ME, et al. Use of livers with microvesicular fat safely expands the donor pool. Transplantation 1997;64:248. [19] Hayashi M, Fujii K, Kiuchi T, Uryuhara K, Kasahara M, Takatsuki M, et al. Effects of fatty infiltration of the graft on the outcome of living-related liver transplantation. Transplant Proc 1999;31:403. [20] Briceno J, Padillo J, Rufian S, Solorzano G, Pera C. Assignment of steatotic livers by the Mayo model for end-stage liver disease. Transpl Int 2005;18:577. [21] Selzner N, Selzner M, Jochum W, Amann-Vesti B, Graf R, Clavien PA. Mouse livers with macrosteatosis are more susceptible to normothermic ischemic injury than those with microsteatosis. J Hepatol 2006;44:694. [22] Urena MA, Ruiz-Delgado FC, Gonzalez EM, Segurola CL, Romero CJ, Garcia IG, et al. Assessing risk of the use of livers with macro and microsteatosis in a liver transplant program. Transplant Proc 1998;30:3288. [23] Yoong KF, Gunson BK, Neil DA, Mirza DF, Mayer AD, Buckels JA, et al. Impact of donor liver microvesicular steatosis on the outcome of liver retransplantation. Transplant Proc 1999;31:550. [24] Cho JY, Suh KS, Kwon CH, Yi NJ, Cho SY, Jang JJ, et al. The hepatic regeneration power of mild steatotic grafts is not impaired in living-donor liver transplantation. Liver Transpl 2005;11:210. [25] Fan ST, Lo CM, Liu CL, Yong BH, Chan JK, Ng IO. Safety of donors in live donor liver transplantation using right lobe grafts. Arch Surg 2000;135:336. [26] McCormack L, Clavien PA. Understanding the meaning of fat in the liver. Liver Transpl 2005;11:137. [27] Hwang S, Lee SG, Jang SJ, Cho SH, Kim KH, Ahn CS, et al. The effect of donor weight reduction on hepatic steatosis for living donor liver transplantation. Liver Transpl 2004;10:721. [28] Selzner N, Rudiger H, Graf R, Clavien PA. Protective strategies against ischemic injury of the liver. Gastroenterology 2003;125:917. [29] Clavien PA, Selzner M, Rudiger HA, Graf R, Kadry Z, Rousson V, et al. A prospective randomized study in 100 consecutive patients undergoing major liver resection with versus without ischemic preconditioning. Ann Surg 2003;238:843. [30] Azoulay D, Del Gaudio M, Andreani P, Ichai P, Sebag M, Adam R, et al. Effects of 10 minutes of ischemic preconditioning of the cadaveric liver on the graft s preservation and function: the ying and the yang. Ann Surg 2005;242:133. [31] Kurihara T, Adachi Y, Yamagata M, Abe K, Akimoto M, Hashimoto H, et al. Role of eicosapentaenoic acid in lipid metabolism in the liver, with special reference to experimental fatty liver. Clin Ther 1994;16:830. [32] Alwayn IP, Andersson C, Zauscher B, Gura K, Nose V, Puder M. Omega-3 fatty acids improve hepatic steatosis in a murine model: potential implications for the marginal steatotic liver donor. Transplantation 2005;79:606. [33] Chui AK, Haghighi K, Painter D, Jayasundera M, Hall G, Rao AR, et al. Donor fatty (steatotic) liver allografts in orthotopic liver transplantation. Transplant Proc 1998;30:3286. [34] Canelo R, Braun F, Sattler B, Klinge B, Lorf T, Ramadori G, et al. Is a fatty liver dangerous for transplantation?. Transplant Proc 1999;31:414. [35] Verran D, Kusyk T, Painter D, Fisher J, Koorey D, Strasser S, et al. Clinical experience gained from the use of 120 steatotic donor livers for orthotopic liver transplantation. Liver Transpl 2003;9:500. doi:10.1016/j.jhep.2006.07.017 Can non-heart-beating donors replace cadaveric heart-beating liver donors? Rahul Deshpande, Nigel Heaton * Kings College London School of Medicine at Kings College Hospital, Institute of Liver Studies, Denmark Hill, Camberwell, London SE5 9RS, UK 1. Introduction * Corresponding author. Tel.: +44 20 73463762; fax: +44 20 73463575. E-mail address: nigel.heaton@kingsch.nhs.uk (N. Heaton). Abbreviations: NHBD, non-heart-beating donor; ICU, intensive care unit Recently non-heart-beating donation (or also called donation after cardiac death) has re-emerged as a major potential way of increasing the supply of organs for transplantation. The success of renal transplantation from non-heart-beating donors (NHBD) [1] has led to

500 Forum on Liver Transplantation / Journal of Hepatology 45 (2006) 483 513 a renewed and wide interest in liver, pancreas and lung retrieval [2,3]. In the early years of transplantation, before the definition and legal acceptance of brain death, NHBD was the principal source of grafts. Following introduction of the concept of irreversible coma [4] and brain death, cadaveric donation gradually replaced NHBD due to the superior results obtained. However, with subsequent improvements in immunosuppression, organ preservation and the standardisation of surgical techniques, liver grafts from NHBD appear to be a valuable new source of organs with significant potential for expansion of the donor pool. 2. Non-heart-beating donation Non-heart-beating donors have been classified into four categories according to the Maastricht criteria (Table 1). The division into controlled and uncontrolled NHBD is helpful as it underlines differences in ethics, clinical practice, graft outcome and future potential between the two groups [5]. Controlled donation occurs in a hospital intensive care unit (ICU) setting in a controlled environment usually with a policy driven planned withdrawal of treatment. In uncontrolled donation, donor death occurs either outside the hospital or in the emergency room following unsuccessful attempts at resuscitation. Most of the current published literature relates to controlled NHBD. The ethics of controlled NHB donation are readily understood and accepted by doctors and the public. There is more time to assess the donors for co-morbidity; they tend to be haemodynamically stable, with normal liver and renal function. The donors are extubated after planned treatment withdrawal either in the ICU or in the operating room. These patients usually have brain injury incompatible with life with rapid cessation of cardiopulmonary function. Warm ischaemia can be accurately assessed and cold ischaemia minimised by prior preparation of a suitable recipient. There is adequate opportunity to counsel both the donor family and the recipient. In comparison to uncontrolled NHBD they tend to be older, have greater co-morbidity and have had organ support on the ICU. It has been estimated that controlled NHBD in its current form has the potential to increase the donor liver pool by at least 20% [6]. Table 1 First International Workshop on non-heart-beating donation, Maastricht, 1994 Categories of non-heart-beating donation (categories 1 and 2, Uncontrolled; 3 and 4, Controlled) 1. Dead on arrival 2. Unsuccessful resuscitation 3. Awaiting cardiac arrest-ventilator switch off 4. Cardiac arrest while brain-dead Uncontrolled NHBD are more likely to be younger and fitter without significant co-morbidity. However, death occurs in an uncontrolled setting, often after prolonged periods of resuscitation, which makes assessment of warm ischaemic time problematic. The legal, ethical and logistic issues that have to be overcome are considerable. However, an approximately twofold net increase in the donor pool has been successfully achieved by a Spanish group [7] and it has been speculated that there is the potential to increase the donor pool by up to 300%. The resources to be invested in such a programme are significant. 3. Reported outcomes after liver transplantation from controlled NHBD (Table 2) All techniques used to procure organs from controlled NHBD aim to keep warm ischaemia to a minimum. A variety of techniques have been utilised including cardiopulmonary bypass with or without cooling, extracorporeal membrane oxygenation and superrapid retrieval as a modification of the en bloc multiorgan harvest technique [3]. Our own technique involves rapid aortic and caval cannulation, topical cooling, aortic clamping and perfusion of the aorta with heparinised Marshall s solution followed by cannulation of the superior mesenteric vein to perfuse the liver with University of Wisconsin solution [6]. The best outcome from controlled NHBD livers has been associated with less than 30 min of warm ischaemia, cold ischaemic times of less than 8 h and donor age of less than 50 years [6,8,9]. A variety of techniques, including pulsatile and non-pulsatile machine perfusion, have been utilised experimentally to try to prolong organ preservations to allow more detailed assessment of the graft. To date there are little clinical data in liver transplantation to identify, which techniques will prevail in the longer term [10]. Early experience of NHBD was associated with inferior patient and graft survival, particularly for the uncontrolled group [3]. Casavilla et al. reported the early Table 2 Outcome after liver transplantation from NHBD Author Year N Pat. survival a Graft survival a Controlled NHBD Muiesan et al. [6] 2005 32 87% 84% Abt et al. [12] 2004 144 79.7% 70.2% Foley et al. [13] 2005 36 80% 67% Manzarbeitia et al. [14] 2004 19 89.5% Uncontrolled NHBD Otero et al. [19] 2004 20 80% (2 yr) 55% (2 yr) Quintela et al. [20] 2005 10 90% (57m) 80% (57m) N, number of patients. a One-year survival, unless otherwise stated.

Forum on Liver Transplantation / Journal of Hepatology 45 (2006) 483 513 501 experience of Pittsburgh with poor graft survival secondary to vascular complications and primary nonfunction. D Alessandro et al. reported a significantly higher incidence of primary non-function (PNF) and worse graft and patient survival in recipients of controlled NHBD [11]. More recently, Abt et al. reported a higher incidence of PNF and retransplantation when compared to HBD [12]. A publication from our own centre reported a single case of PNF in a series of 32 consecutive liver transplants from controlled NHBD [6]. Current experience suggests that the results of controlled NHBD are now approaching those of heart-beating donation (HBD) [6]. Graft and patient survival at one year is 90% and 94%, respectively, in our own institution after 54 liver transplants from controlled NHBD. There are continuing concerns regarding reports of vascular and biliary complications in recipients of controlled NHBD livers. Foley et al. reported a 16.6% incidence of hepatic artery stenosis, 13.8% incidence of biliary stricture and 16.7% incidence of biloma and abscess [13]. There was a high rate of graft loss secondary to these complications. The majority of centres with significant experience of NHBD livers have reported a higher incidence of non-anastomotic biliary strictures. Abt et al. proposed that the increased susceptibility towards ischaemic cholangiopathy was a consequence of longer warm or cold ischaemia times and microcirculatory injury [8]. Manzarbeitia et al. have also reported a higher incidence of vascular complications when compared to brain dead heart-beating donors [14]. Attempts have been made to identify donor and recipient characteristics associated with poor outcome [11]. Prolonged cold ischaemia is associated with graft function and biliary complications. Beyond 12 h graft failure approaching 60% has been reported. Keeping the cold ischaemic time to less than 8 h reduces the graft failure to 10% [11]. Warm ischaemic periods of greater than 30 min have a high risk of graft non-function. Donor age greater than 40 years also appears to increase the risk of graft failure. The choice of recipient may also have a bearing on graft outcome with those on organ support pre-transplant doing less well [11]. It appears that NHBD livers have lower functioning hepatocyte mass and hepatocyte viability in experimental and clinical studies [6]. The development of clinical programmes and the recognition of good controlled NHBD livers has led to the use of liver reduction techniques for successful transplantation of 10 children at our centre [15]. These results suggest that these good donors should not be considered to be marginal. 4. Outcomes after liver transplantation from uncontrolled NHBDs Early results of uncontrolled NHBD were not encouraging. There was a high incidence of PNF and graft loss due to vascular complications [3]. However, studies reported excellent graft and patient survival in kidney recipients [16] and long-term renal function was reported to be better in Maastricht types 1 and 2 as compared to types 3 and 4 [17]. Alvarez et al. using well-defined criteria for accepting uncontrolled NHBD reported good graft function in both transplanted kidneys and livers [18]. Otero et al. reported significantly higher rates of PNF, biliary complications and initial organ dysfunction in 20 liver recipients from uncontrolled NHBD [19]. More recently there have been several case reports of successful uncontrolled NHBD maintained on mechanical chest and abdominal compression, cardio-pulmonary bypass or on ECMO [20]. Wider application and evaluation of these techniques and subsequent graft function are required. 5. The use of NHBD to expand the donor pool What is the potential for NHBD to expand the donor pool and how do we realise them? The results of controlled NHBD are now approaching those obtained with HBD provided that donor age is less than 50 years, warm ischaemia does not extend beyond 30 min and cold ischaemia is kept to a minimum with a cut off of 10 h being accepted as reasonable by the majority of centres. This may increase the donor pool by 20%, better than living donation (which may help 10%), but falling short of what is required. How can graft quality and early function be improved? Warm ischaemia cannot be avoided, but has to be minimised by excellent surgical technique, the use of low viscosity perfusion fluids possibly under pressure (50 mmhg) to clear the microcirculation and thorough flushing of the biliary tree. The use of heparin pre-donation (if allowed) and thrombolytic agents to maintain the microcirculation is considered to improve function and reduce vascular and possibly biliary complications. The need for cold preservation and the subsequent effects of ischaemia/reperfusion injury on the graft are important determinants of graft survival [21]. Experimental studies suggest that pre-treatment of NHBD prior to withdrawal of care may improve outcome by ameliorating ischaemia/reperfusion injuries [22]. A number of agents are being evaluated in experimental studies. The avoidance of cold ischaemia using techniques such as normothermic continuous organ perfusion could expand the safe use of more marginal donors and such models are being developed. Other techniques such as short term hypothermic oxygenated perfusion prior to implantation may also rescue NHBD grafts [23]. The choice of recipient should be restricted to avoid long difficult dissections and possibly those with severe portal hypertension or those on organ support. Techniques of implantation have not been formally evaluated in clinical trials, but clinical experience from small for

502 Forum on Liver Transplantation / Journal of Hepatology 45 (2006) 483 513 Table 3 Prerequisites for establishing a NHBD liver transplant program Controlled NHBD (1) Ensure appropriate legal framework (2) Establish protocols for NHBD retrieval and train donor coordinators and other teams (3) Identify Intensive Care Units and agree protocols for withdrawal of treatment (4) Develop a successful NHBD kidney program followed by liver program, concentrating experience initially within a small team (5) Address consent and allocation issues for NHBD liver transplantation (6) Concentrate on busiest units first with extensive experience of use of marginal grafts and then expand the program Uncontrolled NHBD (1) Establish legal and ethical framework acceptable to the public (2) Carry out public and political consultation with consideration towards presumed consent (opt out) policy for organ donation (3) Develop a regional strategy and funding for 24-h availability of dedicated resuscitation ambulances deployed within defined territories to identify and resuscitate potential donors (4) Establish a robust protocol for cessation of resuscitation, consent issues, donor maintenance and subsequent retrieval (5) Twenty-four-hour availability of a dedicated retrieval team of surgeons, nurses and donor coordinators trained for uncontrolled NHBD (6) Develop cooperation and involvement of the hospital emergence department to establish the program (if possible, develop uncontrolled NHBD after a successful controlled NHBD program) size grafts and experimental studies suggest that alleviation of severe portal hypertension, blood flush and arterial reperfusion may be of value and may extend donor criteria for NHBD. With extended criteria for controlled NHBD it may be possible to expand the potential pool by 30 40% over the next 10 years. To successfully exploit uncontrolled NHBD a number of important obstacles need to be overcome (Table 3). The most pressing is to establish a legal framework that is acceptable to the public. At present uncontrolled NHBD is contentious and considered illegal in many countries. The point when resuscitation becomes futile and organ donation should be considered is not always clear and there are no internationally agreed guidelines. Public acceptance and changes to the law, which allow the use of continuous mechanical chest and abdominal compression, cardiopulmonary bypass techniques or extracorporeal membrane oxygenation whilst family members are consulted, are required. Presumed consent (opt out) helps to provide the appropriate legal framework for this type of donation. The logistics of establishing a programme of uncontrolled donation are also significant. To obtain organs from patients who have collapsed on the street or fail resuscitation in the emergency room requires a dedicated resuscitation ambulance team available 24 h a day able to reach the scene within a very short time [18]. Alvarez et al. reported their experience of 111 potential category 1 uncontrolled NHBD [17]. Of these, 53 were accepted as donors and resulted in the retrieval of 72 kidneys and 12 livers. Of the 12 livers retrieved eight were transplanted with good function. Of note, the median time from cardiac arrest to arrival in hospital was 68 min and to being placed on cardio-pulmonary bypass was 111 min. The assessment of the warm ischaemic time, the effectiveness of resuscitation and the suitability of the donor under these conditions is much more difficult. The initial investment in the training and provision of emergency services is high and the early return relatively low. Effective resuscitation will buy time for assessment of the donor and the potential graft. Reliable tests predicting graft function are needed. Liver biopsy is of limited value and other markers that have been used, which include Glutathione S-transferase and xanthine oxidase, are not reliable indicators of subsequent function. Could NHBD replace HBD? It has been suggested that the absence of brain stem death in NHBD categories 1 3 may be associated with less inflammatory infiltrate in the donor organs and that long-term graft survival may be better. The data are not yet available, but the incidence of acute rejection is currently about 25% (personal observation), certainly no higher than observed for HBD. Data are lacking for long-term outcome in liver recipients, but long-term graft survival in NHBD kidneys is excellent [1]. The early results of liver transplantation from controlled NHBD are approaching those obtained with HBD provided that conservative selection criteria are used. This will supplement the donor pool by 20%, but cannot replace HBD and should be viewed as complementary. Of concern, there may be a trend towards NHDB away from HBD to reduce donor hospital stay and to satisfy the wishes of donor family for cardio-pulmonary death, which may limit the overall increase in organ donation (i.e., a switch from HBD to NHBD as a mode of death). The greatest potential lies with uncontrolled NHBD, but changes are needed from Governments to provide a clear legal framework, funding and training for the infrastructure and acceptance by the public. The development of treatments to preserve, resuscitate and maintain these grafts in the medium term and tests which can accurately assess potential graft function will begin to tap this potential. If successful, NHBD could rival or surpass HBD and living donation as a source of organs for transplantation.

Forum on Liver Transplantation / Journal of Hepatology 45 (2006) 483 513 503 References [1] Weber M, Dindo D, Demartines N, Ambuhl PM, Clavien PA. Kidney transplantation from donors without a heartbeat. N Engl J Med 2002;347:248 255. [2] D Alessandro AM, Hoffmann RM, Knechtle SJ, et al. Successful extra-renal transplantation from non-heart-beating donors. Transplantation 1995;59:977 982. [3] Casavilla A, Ramirez C, Shapiro R, et al. Experience with liver and kidney allografts from non-heart-beating donors. Transplantation 1995;59:197 203. [4] A definition of irreversible coma. Report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death. JAMA 1968;205:337 340. [5] Kootstra G, Daemen JH, Oomen AP. Categories of non-heartbeating donors. Transplant Proc 1995;27:2893 2894. [6] Muiesan P, Girlanda R, Jassem W, et al. Single-centre experience with liver transplantation from controlled non-heartbeating donors: a viable source of grafts. Ann Surg 2005;242:732 738. [7] Alvarez J, del Barrio MR, Arias J, et al. Five years of experience with non-heart-beating donors coming from the streets. Transplant Proc 2002;34:2589 2590. [8] Abt PL, Crawford MD, Desai NM, et al. Liver transplantation from controlled non-heart-beating donors: an increased incidence of biliary complications. Transplantation 2003;75:1659 1663. [9] Monbaliu D, Crabbe T, Roskams T, et al. Livers from non-heartbeating donors tolerate short periods of warm ischemia. Transplantation 2005;79:1226 1230. [10] Uchiyama M, Matsuno K, Hama H, et al. Comparison between nonpulsatile and pulsatile machine perfusion preservation in liver transplantation from non-heart-beating donors. Transplant Proc 2001;33:936 938. [11] D Alessandro AM, Fernandez LA, Chin LT, et al. Donation after cardiac death: the University of Wisconsin experience. Ann Transplant 2004;9:68 71. [12] Abt PL, Desai NM, Crawford MD, et al. Survival following liver transplantation from non-heart-beating donors. Ann Surg 2004;239:87 92. [13] Foley DP, Fernandez LA, Leverson G, et al. Donation after cardiac death: the University of Wisconsin experience with liver transplantation. Ann Surg 2005;242:724 731. [14] Manzarbeitia CY, Ortiz JA, Jeon H, et al. Long-term outcome of controlled, non-heart-beating donor liver transplantation. Transplantation 2004;78:211 215. [15] Muiesan P, Jassem W, Girlanda R, et al. Segmental liver transplantation from non-heart beating donors an early experience with implications for the future. Am J Transplant 2006;6:1012 1016. [16] Nicholson ML, Metcalfe MS, White SA, et al. A comparison of the results of renal transplantation from non-heart-beating, conventional cadaveric, and living donors. Kidney Int 2000;58:2585 2591. [17] Sanchez-Fructuoso AI, de Miguel Marques, Prats D, et al. Nonheart-beating donors: experience from the Hospital Clinico of Madrid. J Nephrol 2003;16:387 392. [18] Alvarez J, del Barrio R, Arias J, et al. Non-heart-beating donors from the streets: an increasing donor pool source. Transplantation 2000;70:314 317. [19] Otero A, Gomez-Gutierrez M, Suarez F, et al. Liver transplantation from Maastricht category 2 non-heart-beating donors: a source to increase the donor pool?. Transplant Proc 2004;36:747 750. [20] Quintela J, Gala B, Baamonde I, et al. Long-term results for liver transplantation from non-heart-beating donors maintained with chest and abdominal compression-decompression. Transplant Proc 2005;37:3857 3858. [21] Reddy S, Greenwood J, Maniakin N, et al. Non-heart-beating donor porcine livers: the adverse effect of cooling. Liver Transpl 2005;11:35 38. [22] Fukunaga K, Takada Y, Taniguchi H, et al. Endothelin antagonist treatment for successful liver transplantation from non-heart-beating donors. Transplantation 1999;67:328 332. [23] Dutkowski P, Graf R, Clavien PA. Rescue of the cold preserved rat liver by hypothermic oxygenated machine perfusion. Am J Transplant 2006;6:903 912. doi:10.1016/j.jhep.2006.07.018 How can donors with a previous malignancy be evaluated? Joseph F. Buell *, Rita R. Alloway, E. Steve Woodle The University of Cincinnati, Division of Transplantation, Cincinnati, OH, USA 1. Introduction Solid organ transplantation has flourished over the last three decades with improvements in surgical technique and modern immunosuppression resulting in * Corresponding author. Tel.: +1 513 558 6010; fax: +1 513 558 3580. E-mail address: Joseph.buell@uc.edu (J.F. Buell). Abbreviations: OPTN, Organ Procurement and Transplantation Network; UNOS, united network for organ sharing; DCIS, ductal carcinoma in situ. improved patient outcomes. Traditionally, solid organ transplantation has been limited by organ availability. The principal source of these organs has been cadaveric donation. A steady increase in organ donation was observed in the early 1990s realized through public awareness and education programs [1]. Concurrently several surgical innovations in live donor kidney, pancreas, liver and intestinal transplantation have also contributed to an increase in transplants. However, both efforts have appeared to have achieved a plateau in the last few years.